Cannabinoid receptor ligands

1. A compound having the formula II,

or a pharmaceutically acceptable salt thereof, wherein R 1 , L 1 , M 1 , M 2 , Y and Z are selected from the groups consisting of:

R 1

L 1

M 1 -Y

—CH(CH 3 ) 2

—CH 2 —

—CH(CH 3 ) 2

—CH 2 —

—CH(CH 3 ) 2

—CH 2 —

—CH(CH 3 ) 2

—CH 2 —

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—CH 2 —

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—N(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

Covalent bond

—CH(CH 3 ) 2

—S(O 2 )—

—S(O 2 )—

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—S(O 2 )—

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—S(O 2 )—

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—OCH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

—CH(CH 3 ) 2

—S(O 2 )—

M 2 -Z

Y

Z

—CF 3

F,

—CF 3

—OCF 3

F,

—OCF 3

—NH(CH 2 ) 2 OH,

—OCF 3

—CH 3 ,

—OCF 3

F,

—OCF 3

H,

H

F,

—OCF 3

H,

H

F,

Cl

F,

H

H,

N(CH 2 ) 2

F,

H

H,

—CH(CH 3 ) 2

H,

—N(CH 3 ) 2

H,

—CH(CH 3 ) 2

H,

OH

F,

F,

—CH(CH 3 ) 2

—CH 3 ,

H,

—CH(CH 3 ) 2

H,

—OCH 3

H,

—CH(CH 3 ) 2

H,

—CH(CH 3 ) 2

H,

H,

H,

—CN

H,

H,

—CF 3

H,

H

F,

—OCF 3

F,

—OCH 3

H,

—OCH 3

F,

H,

—CH(CH 3 ) 2

H,

—OCH(CH 3 ) 2

F,

—OCH(CH 3 ) 2

H,

—CH(CH 3 ) 2

H,

—OCH(CH 3 ) 2

—COOCH 3 ,

H

F,

H

H,

H

H,

—CF 3

H, and

H

H.

2. A compound having the formula III:

or a pharmaceutically acceptable salt thereof, wherein

Y is selected from the group consisting of hydrogen, alkoxy, alkyl, —CF 3 , cycloalkyl, halogen, —OCF 3 and —OH;

Z is selected from the group consisting of hydrogen, alkyl, —CF 3 , halogen, —N(R 2 ) 2 , —OCF 3 and —OH; and

M 2 is aryl or heteroaryl.

3. The compound having the formula:

or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

5. A pharmaceutical composition comprising an effective amount of at least one compound according to claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. A process for making a pharmaceutical composition comprising combining at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

7. A process for making a pharmaceutical composition comprising combining at least one compound of claim 2 , or a pharmaceuticaily acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

8. A method of treating inflammatory diseases, immunomodulatory diseases, or respiratory diseases comprising administering to a mammal in need of such treatment an effective amount of at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

9. A method of treating inflammatory diseases, immunomodulatory diseases, or respiratory diseases comprising administering to a mammal in need of such treatment an effective amount of at least one compound according to claim 2 , or a pharmaceutically acceptable salt thereof.

10. A method of treating rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, glaucoma, diabetes, sepsis, shock, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scieroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, Crohn's disease, inflammatory bowel disease, reversible airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) or bronchitis comprising administering to a mammal in need of such treatment an effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. A method of treating rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, glaucoma, diabetes, sepsis, shock, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, cerebral stroke, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, Crohn's disease, inflammatory bowel disease, reversible airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) or bronchitis comprising administering to a mammal in need of such treatment an effective amount of at least one compound according to claim 2 or a pharmaceutically acceptable salt thereof.

12. The method of claim 8 wherein the condition or disease treated is selected from rheumatoid arthritis, multiple sclerosis, seasonal allergic rhinitis, psoriasis, transplant rejection and chronic obstructive pulmonary disease.

13. The method of claim 9 wherein the condition or disease treated is selected from rheumatoid arthritis, multiple sclerosis, seasonal allergic rhinitis, psoriasis, transplant rejection and chronic obstructive pulmonary disease.

14. A process for making a pharmaceutical composition comprising combining at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

15. A process for making a pharmaceutical composition comprising combining at least one compound of claim 2 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

16. A method of treating rheumatoid arthritis comprising administering to a mammal in need thereof an effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with at least one compound selected from the class consisting of a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, an anti-TNF-α compound or other classes of compounds indicated for the treatment of rheumatoid arthritis.

17. A method of treating rheumatoid arthritis comprising administering to a mammal in need thereof an effective amount of at least one compound of claim 2 , or a pharmaceutically acceptable salt thereof, in combination with at least one compound selected from the class consisting of a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, an anti-TNF-α compound or other classes of compounds indicated for the treatment of rheumatoid arthritis.

18. The method of claim 16 wherein the COX-2 inhibitor is Celebrex or Vioxx, the COX-1 inhibitor is Feldene, the immunosuppressive is methotrexate, leflunomide, sulfasalazine, or cyclosporin, the steroid is β-methasone and the anti-TNF-α compound is Enbrel or Remicade.

19. The method of claim 17 wherein the COX-2 inhibitor is Celebrex or Vioxx, the COX-1 inhibitor is Feldene, the immunosuppressive is methotrexate, leflunomide, sulfasalazine, or cyclosporin, the steroid is β-methasone and the anti-TNF-α compound is Enbrel or Remicade.

20. A composition for treating rheumatoid arthritis which comprises a compound selected from the class consisting of a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, an anti-TNF-α compound or other classes of compounds indicated for the treatment of rheumatoid arthritis and an effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof.

21. A composition for treating rheumatoid arthritis which comprises a compound selected from the class consisting of a COX-2 inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, an anti-TNF-α compound or other classes of compounds indicated for the treatment of rheumatoid arthritis and an effective amount of at least one compound of claim 2 , or a pharmaceutically acceptable salt thereof.

22. The composition of claim 20 wherein the COX-2 inhibitor is Celebrex or Vioxx, the COX-1 inhibitor is Feldene, the immunosuppressive is methotrexate, leflunomide, sulfasalazine, or cyclosporin, the steroid is β-methasone and the anti-TNF-α compound is Enbrel or Remicade.

23. The composition of claim 21 wherein the COX-2 inhibitor is Celebrex or Vioxx, the COX-1 inhibitor is Feldene, the immunosuppressive is methotrexate, leflunomide, sulfasalazine, or cyclosporin, the steroid is β-methasone and the anti-TNF-α compound is Enbrel or Remicade.

24. A method of treating multiple sclerosis comprising administering to a mammal in need thereof an effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a compound selected from Avonex, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis.

25. A method of treating multiple sclerosis comprising administering to a mammal in need thereof an effective amount of at least one compound of claim 2 , or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a compound selected from Avonex, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis.

26. A composition for treating multiple sclerosis which comprises a compound selected from Avonex, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis and an effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof.

27. A composition for treating multiple sclerosis which comprises a compound selected from Avonex, Betaseron, Copaxone or other compounds indicated for the treatment of multiple sclerosis and an effective amount of at least one compound of claim 2 , or a pharmaceutically acceptable salt thereof.

28. A method of treating psoriasis comprising administering to a mammal in need thereof an effective amount of at least one compound as defined in claim 1 , or a pharmaceuticallv acceptable salt thereof, in combination with a compound selected from the class consisting of an immunosuppressive, a steroid, an anti-TNF-α compound or other classes of compounds indicated for the treatment of psoriasis.

29. A method of treating psoriasis comprising administering to a mammal in need thereof an effective amount of at least one compound as defined in claim 2 , or a pharmaceutically acceptable salt thereof, in combination with a compound selected from the class consisting of an immunosuppressive, a steroid, an anti-TNF-α compound or other classes of compounds indicated for the treatment of psoriasis.

30. The method of claim 28 wherein the immunosuppressive is methotrexate, leflunomide, sulfasalazine or cyclosporin, the steroid is β-methasone and the anti-TNF-α compound is Enbrel or Remicade.

31. The method of claim 29 wherein the immunosuppressive is methotrexate, leflunomide, sulfasalazine or cyclosporin, the steroid is β-methasone and the anti-TNF-α compound is Enbrel or Remicade.

32. A composition for treating psoriasis which comprises a compound selected from the class consisting of an immunosuppressive, a steroid, an anti-TNF-α compound or other classes of compounds indicated for the treatment of psoriasis and an effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof.

33. A composition for treating psoriasis which comprises a compound selected from the class consisting of an immunosuppressive, a steroid, an anti-TNF-α compound or other classes of compounds indicated for the treatment of psoriasis and an effective amount of at least one compound of claim 2 , or a pharmaceutically acceptable salt thereof.

34. The composition of claim 32 wherein the immunosuppressive is methotrexate, leflunomide, sulfasalazine or cyclosporin, the steroid is β-methasone and the anti-TNF-α compound is Enbrel or Remicade.

35. The composition of claim 33 wherein the immunosuppressive is methotrexate, leflunomide, sulfasalazine or cyclosporin, the steroid is β-methasone and the anti-TNF-α compound is Enbrel or Remicade.

36. A method of treating seasonal allergic rhinitis and/or asthma comprising an effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with at least one H1 antagonist.

37. A method of treating seasonal allergic rhinitis and/or asthma comprising an effective amount of at least one compound of claim 2 , or a pharmaceutically acceptable salt thereof, in combination with at least one H1 antagonist.

38. A composition for treating seasonal allergic rhinitis and/or asthma which comprises an effective amount of at least one H1 antagonist and an effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof.

39. A composition for treating seasonal allergic rhinitis and/or asthma which comprises an effective amount of at least one H1 antagonist and an effective amount of at least one compound of claim 2 , or a pharmaceutically acceptable salt thereof.

40. The composition of claim 38 wherein the H1 antagonist is selected from Claritin, Clarinex, Zyrtec and Allegra.

41. The composition of claim 39 wherein the H1 antagonist is selected from Claritin, Clarinex, Zyrtec and Allegra.

42. A pharmaceutical composition comprising at least one compound according to claim 3 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

43. A process for making a pharmaceutical composition comprising combining at least one compound of claim 3 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

44. A method of treating inflammatory diseases, immunomodulatory diseases, or respiratory diseases comprising administering to a mammal in need of such treatment an effective amount of at least one compound according to claim 3 , or a pharmaceutically acceptable salt thereof.